Early-onset gynecological tumors in DNA repair-deficient xeroderma pigmentosum group C patients: a case series

Background Xeroderma pigmentosum (XP) is a group of rare hereditary disorders with highly increased risk of skin tumors due to defective DNA repair. Recently we reported 34-fold increased risk of internal tumors in XP patients in comparison with general population. The molecular data and clinical practice on the internal tumors treatment in XP patients is limited and scarcely represented in the medical literature. In this work, we describe young patients with constitutive biallelic deactivation of the XPC gene developing gynecological tumors with somatic DICER1 mutations. Methods Whole genome sequencing was used to analyze in detail somatic mutational landscape and driver events of these rare tumors. Results We describe five early-onset gynecological tumors in four xeroderma pigmentosum group C (XP-C) young patients (11 to 19 years old) including vaginal embryonal rhabdomyosarcomas in monozygotic twin sisters, juvenile granulosa-cell tumor of the ovary and poorly differentiated stage IA Sertoli-Leydig cell tumor in 19-years old patient, and FIGO stage IC1 tumor of ovary in 13-years old patient. XP-C ovarian tumors harbor 4.4 times more single base substitutions than sporadic tissue-matched cancers and demonstrate XP-C specific mutation signature with strong transcriptional bias indicating inability of the cells to repair bulky DNA lesions of unknown etiology. A special mode of treatment was applied to avoid usage of chemotherapy which is toxic for XP patients. Conclusions XP-C status should be accounted for prevention and specific treatment of gynecological tumors in young DNA repair-deficient XP patients.

In this manuscript, Yurchenko et al. evaluated the genomic profile (germline and somatic) of 5 gynecological tumors from XP-C patients. They found a DICER1 mutation in all tumors and a specific mutation signature of XP-C patients and GG-NER deficiency. The clinical description was very welldetailed for all patients. This study also highlights that patients harboring DNA repair deficiency should be accounted for before the treatment to minimize adverse effects, mostly in young patients. This is a well-documented study with findings of the impact that increase our knowledge of this rare disease. I have a few comments: 1.Reference 2: should be presented with complete information. Yurchenko AA, Padioleau I, Matkarimov BT, Soulier J, Sarasin A, Nikolaev S. XPC deficiency increases risk of hematologic malignancies through mutator phenotype and characteristic mutational signature. Nat Commun. 2020 Nov 17;11(1):5834. doi: 10.1038/s41467-020-19633-9. PMID: 33203900; PMCID: PMC7672101.
2.It is curious that DICER mutation was found in all tumors of the 4 XP-C patients. Although the authors stated that this event is common in ERMS and SLCT, having a hypothesis or plausible explanation for these findings will be interesting.

Reviewer #2 (Remarks to the Author):
This manuscript is a case report on 5 early-onset gynecological tumors in 4 xeroderma pigmentosum (XP) patients. One of the greatest strengths of this paper is the report on monozygotic twin sisters who carried homozygous c.1643_1644delTG; p.Val548Alafs25 pathogenic variant in the XPC gene and who developed embryonal rhabdomyosarcoma (vERMS) both at age 16 is of great interest. Both had similar clinical presentation and shared the same histological analysis. Nevertheless, recovery was complete to one of the twins, with a follow-up of 10 years, whereas the other twin developed an acute myeloid leukemia at the age of 20, a year later total aplasia and died at 22. This is a novel description of identical twins carrying the same germline XPC pathogenic variant and it represents a perfect human model that might provide insights on the understanding on what are the underlying interacting genetic factor that lead XPC carriers of the same mutation develop the exact same tumor at the same age. A minor limitation need to be addressed. The manuscript has a poor clinical presentation of all included cases. A thorough description on tumor spectrum and age of onset should be provided as well as the description of other typical features of the syndrome. The work is convincing and it is a very well written paper suitable for publication after the addition of a table containing the clinical profile of all 5 cases.

Reviewers' comments:
Reviewer #1 (Remarks to the Author): In this manuscript, Yurchenko et al. evaluated the genomic profile (germline and somatic) of 5 gynecological tumors from XP-C patients. They found a DICER1 mutation in all tumors and a specific mutation signature of XP-C patients and GG-NER deficiency. The clinical description was very well-detailed for all patients. This study also highlights that patients harboring DNA repair deficiency should be accounted for before the treatment to minimize adverse effects, mostly in young patients. This is a welldocumented study with findings of the impact that increase our knowledge of this rare disease.
I have a few comments: 1.Reference 2: should be presented with complete information.

2.It is curious that DICER mutation was found in all tumors of the 4 XP-C patients.
Although the authors stated that this event is common in ERMS and SLCT, having a hypothesis or plausible explanation for these findings will be interesting.
Response: we thank the reviewer for this comment and agree that presence of DICER1 mutations in all the tumor samples is an interesting result. Unfortunately, the low number of cases with genomic analysis preclude us from making a strong hypothesis.
There is a possibility that a specific mutational process observed in the cancers of XPC patients can favor DICER1 damaging mutations which are important in gynecological cancers but we do not have a strong evidence for that yet. Encouraged by the reviewer we shortly expanded the Discussion section (L262-266).

Reviewer #2 (Remarks to the Author):
This manuscript is a case report on 5 early-onset gynecological tumors in 4 xeroderma pigmentosum (XP) patients. One of the greatest strengths of this paper is the report on monozygotic twin sisters who carried homozygous c.1643_1644delTG; p.Val548Alafs25 pathogenic variant in the XPC gene and who developed embryonal rhabdomyosarcoma (vERMS) both at age 16 is of great interest. Both had similar clinical presentation and shared the same histological analysis. Nevertheless, recovery was complete to one of the twins, with a follow-up of 10 years, whereas the other twin developed an acute myeloid leukemia at the age of 20, a year later total aplasia and died at 22. This is a novel description of identical twins carrying the same germline XPC pathogenic variant and it represents a perfect human model that might provide insights on the understanding on what are the underlying interacting genetic factor that lead XPC carriers of the same mutation develop the exact same tumor at the same age. \ Response: we thank the reviewer for the encouraging summary of our work.
A minor limitation need to be addressed. The manuscript has a poor clinical presentation of all included cases. A thorough description on tumor spectrum and age of onset should be provided as well as the description of other typical features of the syndrome.
The work is convincing and it is a very well written paper suitable for publication after the addition of a Authors have adequately responded to all questinings and have added Table 1 which summarizes the clinical profiles of the patients as well as additional information to the text of the manuscript. Tha manuscript reads very well, results are of importance in a field where information on XP is scarce and it addresses a population which is extremely rare.